What is CRISPR?

Clustered regularly interspaced short palindromic repeats, or CRISPR, is a gene-editing technology that allows scientists to make manual changes to our DNA with incredible precision, allowing us to deal with genetic illnesses and crop modification in timescales previously thought impossible. In 2020, its pioneers, Jennifer Doudna and Emmanuelle Charpentier, were awarded the Nobel Prize in Chemistry for their groundbreaking work on it. But CRISPR also raises ethical questions and potential dangers. Could it lead to designer babies and unintended mutations? And would life changing treatments be doled out equally for everyone? First though, what exactly is CRISPR, and where did it come from? NYU’s Neville Sanjana...

Neville - One of the key breakthroughs, which I find really fascinating, came from food scientists working on yoghurt production. These food scientists were tasked with understanding why certain bioreactors failed to culture yoghurt. Very practical problem, you know, we have invested all this money, we put all these raw materials in, we need to make yoghurt at scale, but occasionally we're getting these failures. What's going on? And this is how they discovered that CRISPR in its natural role is an adaptive immune system in bacteria. It protects the bacteria from phages, which are a type of virus that can attack bacteria. CRISPR enables bacteria to store a memory of a phage that it's previously seen, it stores a tiny bit of the phage genome, and this CRISPR system can protect the bacteria when that same phage or a similar phage comes back to attack and try to infect the bacterial cells.

Will - So was the idea, then, that we looked at these bacteria and went, 'they're snipping viral genomes at certain points and storing them so that they can remember them when the virus comes back later. What if we could use those same scissors?'

Neville - It's exactly that. So we can take CRISPR and instead of just using it in the way that the bacteria use it to protect themselves from phage, we can take advantage of its programmability and redirect these CRISPR systems to target anywhere, even in a large genome like a human genome. Because it's such a programmable system, it can be moved into really any other organism and reprogrammed using a small piece of RNA called a guide RNA. And that's something that can easily be made in the lab or bought. So it's easy to direct those CRISPR scissors to any place in the genome. And it's really the programmability that led to that widespread adoption of CRISPR.

Will - So we have these biological scissors with which we can go into a faulty genome and snip a bit out or alter a bit or delete a bit as is necessary.

Neville - That's right. So the scissors themselves actually stimulate the endogenous repair pathways because it's very important for all living organisms to be able to repair anything that happens to their DNA. And so what you can think of is that it takes two to tango. So the CRISPR scissors go in there and they make the cut and that cut calls the repair proteins to this particular site. And using that we can either delete a gene or we can add a few bases in or we can make a very precise edit to change maybe a variant that leads to a particular disease to a non-pathogenic variant.

Will - What do we use CRISPR for?

Neville - One of the practical uses of it is definitely to develop therapeutics that could edit in somatic cells, that's adult cells, genetic variants. So if somebody carries a variant for a severe genetic disease we want to be able to correct that disease. That's the dream of this one and done therapy. Instead of a drug that you need to take continually you can give them a gene editing therapy that they take once and then from that point on that disease no longer impacts them. That's one of the main uses of CRISPR. There are other uses of CRISPR for editing genomes that are not human genomes like plant genomes. Plants have notably complex genomes with many many copies of different genes and the ways that particular traits have been bred over decades and centuries has led to very inbred crops which is great because we have those traits in particular crops but those crops, because they're inbred, are maybe not hardy or resistant to climate change and so could we transfer some of the desirable traits that have been accumulated over the years through human agricultural breeding and transfer them to other strains that might be more hardy and resistant to climate change.

Will - Where do you come into it? What does your work with CRISPR involve?

Neville - My work focuses on understanding the human genome, the genes in it and all the rest of the genome. The other 99% of the genome that's not genes non-coding elements that regulate gene expression. There are 20,000 genes in the human genome and let's say we want to find which of those 20,000 genes are important for cancer growth. If we test each gene one by one it's almost an impossible task. You know you need an army of robots or an army of graduate students and post-doctoral fellows and staff scientists and everybody here. But with CRISPR we can actually target all 20,000 genes in one single experiment and measure the effects on cancer growth. So if we have six different CRISPRs for a gene we can say okay I've knocked this gene out in six different ways and six different cells and look they all have the same effect. One of the earliest CRISPR screens we did examined a region of the human genome that's important for switching between different forms of haemoglobin, a protein that carries oxygen in red blood cells. Using a few thousand CRISPRs we found a part of the genome that switches blood cells back to using foetal haemoglobin, something we normally only make right up until the time we're born. But this is very useful because some people with diseases like sickle cell  anaemia have problems with adult haemoglobin. They have a defect in the adult haemoglobin. A biotech company just a few years later was able to modify the blood cells of someone here in the United States. Her name is Victoria Gray and she became the first person to be cured of sickle cell  anaemia using CRISPR and about a year ago this treatment became the first FDA approved gene editing therapy of any kind. That's just kind of a bonkers thing to think about. It's absolutely amazing that we can go from basic discovery to an approved cure with a totally new modality of therapy for a painful disease that impacts millions of people and do that all in less than a decade.